Persistent viral infections (e.g. HIV, Hepatitis B & C) represent a significant source of morbidity and mortality with over 500 million persons infected worldwide. The underlying mechanisms that promote persistent viral infection remain incompletely understood. We use a mouse model of viral infection with lymphocytic choriomeningitis virus (LCMV) to define fundamental virus-host interactions that can tip the balance toward resolution and clearance of persistent infection. The site-1 Protease (S1P) is a host protein required late in the arenavirus life cycle to produce infectious LCMV and other hemorrhagic arenaviruses that cause rapid fatality after aerosol contact. We generated mice conditionally deficient for S1P in targeted cell types to define the role of productive viral infection in antigen presenting cells (APC) during persistent viral infection. Using this approach, we identified dendritic cells (DC) as key cell types where productive viral replication is required for persistent systemic infection. This observation highlights a potential Achilles' heel for persistent viral infection where one may target only a single specific cell type to eliminate overall persistent viral infection. Overall Hypothesis: We propose that persistent viral infections specifically engage APC and subvert their function to persist-effectively turning the host's immune sentinels into viral factories that exhaust rather than activate the antiviral T cell response. A corollary to this hypothesis is that by blocking the viral life cycle in DC we can activate DC (Aim 1) to drive the otherwise exhausted LCMV-specific T cell response in vivo (Aim 2). Obtaining this knowledge will increase our understanding of persistent infections and how to treat them. We will delete genetically delete S1P in DC to determine its function during chronic viral infection. More specifically, we will determine the rol of host S1P in generating fully processed LCMV glycoprotein and subsequently infectious arenavirus from DC. We will be able to do this efficiently and in vivo by using recombinant virus with a complementing mutation in its glycoprotein cleavage site. This complementing mutation will allow growth of the recombinant virus in S1P deficient cells. Our Specific Aims will identify cell-specific molecular mechanism. We will determine the effector molecules modulated in an S1P-dependent fashion during viral infections and subsequently demonstrate their relative sufficiency in conferring susceptibility or resistance to infection via altering APC-T cell interactions. We propose to mechanistically delineate how a viral protein (e.g. GPC) inhibits the host response at a molecular level. This information is significant for potential application to modify inappropriate immune responses in patients. In summary, this application not only addresses a basic biological question of why viral infections persist, it also outlines a significat translational strategy for controlling or eliminating persistent viral infection by specific modification of APC. By delineating mechanism, the fruits of these studies may be used to modify immune responses in patients undergoing infectious and/or immune-mediated diseases.